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Malonic dialdehyde has a pronounced central vasoconstrictor effect, though when given in large doses, it causes a profound decrease in systemic blood pressure, however its vasoconstrictor effects are not directly related to fluctuations in systemic blood pressure. The universal antioxidant alpha-tocopherol acetate abolishes and prevents the central vasoconstrictor effects of malonic dialdehyde.
We have compared the response of small subcutaneous resistance arteries from 15 mild essential hypertensive patients and 13 normotensive controls to various potentially pathophysiologically important vasoconstrictors. Blood vessels obtained from gluteal subcutaneous biopsies from hypertensive patients exhibited a significantly smaller external diameter and lumen and greater media/lumen ratio than those of normotensive subjects, but no significant difference in media thickness or cross-sectional area. Vasoconstrictor peptides produced varying effects on resistance arteries of hypertensive patients relative to controls: angiotensin II and arginine vasopressin elicited normal active media stress responses, while the contractile effect of endothelin-1 was depressed. Norepinephrine media stress responses were also blunted in hypertensive patients. Cocaine produced a shift to the left of the norepinephrine dose-response in vessels from both controls and hypertensive patients. Since the lumen diameter of blood vessels was reduced in hypertensive patients, vasoconstrictor responses were amplified, resulting in calculated pressor responses to endothelin-1 similar to those of normotensive controls. These results demonstrate the structural and functional alterations present in resistance arteries of mild essential hypertensive patients, which may be involved in maintaining elevated blood pressure.
The vasoconstrictors norepinephrine (NE) and angiotensin II (AII) mediate increases in oxygen uptake (VO2) by the constant flow perfused rat hind limb that are inhibited by quinidine-like membrane-stabilizing effects (involving the interruption of action potential) of (+/-)-propranolol with little effect on vasoconstriction. The membrane labilizer veratridine, 10 microM, which has the capability of maintaining voltage-gated Na+ channels of the plasma membrane in their open state, also increases VO2 but without an increase in pressure. Thus in the present study veratridine was characterized in detail and compared with NE in the same system. Veratridine (3-100 microM) produced a dose-dependent stimulation of VO2 (from 11.8 +/- 0.3 to 20.4 +/- 0.6 mumol.h-1.g-1 (n = 5), p < 0.0001) and lactate efflux (LE) (from 7.4 +/- 0.6 to 23.0 +/- 4.7 mumol.h-1.g-1 (n = 5), p < 0.01). These increases were independent of vasoconstriction at low doses (< or = 10 microM). At higher doses of veratridine the accompanying minor vasoconstriction (from 17 +/- 1 to 30 +/- 2 mmHg (1 mmHg = 133.3 Pa) (n = 5), p < 0.005) was blocked by sodium nitroprusside (NP) while neither VO2 nor LE was greatly affected. Low Na+ perfusions (25 mM) did not affect the vasoconstrictor action of NE but markedly inhibited increases in VO2 and LE due to either veratridine or NE. Veratridine (10 microM) mediated increases in VO2 and LE were blocked by either (+/-)-propranolol (100 microM) or 150 microM quinidine. It is concluded that vasoconstrictors such as NE, which stimulate VO2 in the perfused rat hind limb, do so by a two-stage process involving an essential nitroprusside-sensitive redirection of flow followed by a mechanism involving increased ion movement across skeletal muscle cell membranes, which is blocked by membrane stabilizers. Veratridine achieves a similar increase in VO2 but may do so by directly destabilizing the skeletal muscle cell membrane without the requirement of a redirection of flow.
There is little in the literature to support recommendations for the use of steroids and vasoconstrictors in the treatment of postintubation croup. We developed a ferret model to study this condition. Ninety-eight ferrets were used in these experiments, which were undertaken to evaluate the efficacy of steroids and/or a long-acting vasoconstrictor, to develop dose-response curves for dexamethasone sodium phosphate if it proved efficacious, and to evaluate the possible synergistic effects of combination therapy. With this animal model, we were able to document a statistically significant early effect of dexamethasone sodium phosphate, but only when administered in large doses (greater than 0.5 mg/kg). Our data also support the tapering of these large doses within a 20-hour period. The long-acting vasoconstrictor oxymetazoline hydrochloride has a clear and statistically significant beneficial effect that is apparent by 20 hours and continues through 40 hours. We did not find any additive or synergistic effect of the combination of dexamethasone and oxymetazoline. Further studies are underway in our laboratory to elucidate other aspects of this interesting syndrome.
The duration of the coronary artery vasoconstrictor effect of ergonovine maleate is an important clinical parameter that has not been clearly defined. Since ergonovine is generally administered in incremental, cumulative doses and since this agent may have potentially serious toxic effects related to its vasoconstrictor properties, knowledge of duration of this effect is crucial to its safe and efficacious use. We present clinical evidence of ergonovine-induced coronary artery spasm recurring after pharmacologic relief of a first episode of ergonovine-induced spasm. Recurrent spasm occurred 18 minutes after a cumulative dose of 0.15 mg ergonovine and 14 minutes after intravenous nitroglycerin was given to ameliorate the initial spasm. Therefore, clinical monitoring of patients after ergonovine administration should be designed to identify a possibly prolonged duration of vasoconstrictor effect of the drug. Sequential doses of ergonovine at intervals of ten minutes or less should be recognized as having cumulative effect. The duration of action of pharmacologic agents utilized to alleviate ergonovine-induced coronary artery spasm should exceed the potential duration of action of ergonovine in order to minimize the possibility of late spasm.
We recently reported that vasopressin analogues correct the in vitro vascular hyporeactivity to adrenergic vasoconstrictors in portal hypertensive rats. The aim of the present study was to determine whether vasopressin reduces splanchnic blood flow in portal vein-ligated (PVL) rats by restoring vasoconstrictor responsiveness in vivo. The ultrasonic transit time-shift technique was used for blood flow measurements. At basal conditions, blood flow through the superior mesenteric artery was elevated 1.6-fold in PVL rats as compared with sham-operated (SHAM) control rats. PVL rats also exhibited blunted mesenteric constrictor responses to the adrenoceptor agonist, phenylephrine (0.03-1 micromol x min(-1) x kg(-1)). Terlipressin (2-20 microg x k(-1)) and arginine vasopressin (3-300 pmol x min(-1) x kg(-1)) dose-dependently reduced, and at the highest doses, even abolished, the difference in mesenteric blood flow (MBF) between PVL and SHAM rats. When expressed as percent changes relative to baseline, mesenteric arterial responses to terlipressin and arginine vasopressin were found to be enhanced in PVL rats as compared with SHAM rats. Moreover, pretreatment with terlipressin (20 microg x kg(-1)) reversed the mesenteric hyporesponsiveness to phenylephrine of PVL rats. These vasopressin effects were independent of the nitric oxide (NO) pathway, because they were not mimicked by inhibition of NO synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME) (0.1-10 mg x kg(-1)). These data indicate that pharmacological doses of vasopressin reverse the splanchnic hyperemia by restoring the responsiveness to adrenergic vasoconstrictors in portal hypertensive rats.
Subcutaneous and skeletal muscle blood flow in the forearm during 30 degrees head-up tilt was studied in 15 healthy subjects before and during treatment with propranolol. Relative blood flow was estimated by the local 133Xe washout technique. Head-up tilt elicited greater vasoconstriction in both tissues during beta-receptor blockade as compared to the pretreatment period. Proximal nerve blockade with lidocaine prevented the vasoconstrictor response in subcutaneous tissue to the tilt. In skeletal muscle injection of a low dose of propranolol had no effect on the vasoconstrictor response to tilt. Therefore, the augmented vasoconstrictor response to head-up tilt during beta-receptor blockade is most probably due to centrally elicited (baroreceptor) and neurogenically mediated impulses to resistance vessels in peripheral tissues and not to "unmasking" of peripheral alpha-receptors.
Stimulation of the sympathetic outflow (spinal cord segments T 7-9) in pithed rats resulted in an increase in mean arterial pressure, heart rate, total peripheral vascular resistance and cardiac output. The increase in blood pressure and peripheral resistance was markedly depressed by prazosin and to a lesser extent by yohimbine, suggesting that these responses were mediated primarily by postjunctional alpha 1-adrenoceptors. The calcium entry blockers nifedipine, tiapamil and verapamil also depressed pressor responses and the increase in total peripheral resistance to electrical stimulation of the sympathetic outflow in these rats. This depression resulted primarily from an effect on peripheral vascular resistance components, as cardiac output remained unaffected by the calcium entry blockers. This conclusion was supported by studies on isolated, perfused rat renal arteries. Vasoconstrictor responses of this in vitro preparation to perivascular nerve stimulation were depressed by 1,000-fold lower concentrations of prazosin than rauwolscine, demonstrating the predominantly alpha 1-adrenoceptor nature of these effects. Likewise, these vasoconstrictor responses were depressed by nifedipine, tiapamil and verapamil in a concentration-dependent manner. The results of this study suggest that vasoconstrictor responses of rat resistance vessels to sympathetic nerve stimulation are mediated primarily by postjunctional alpha 1-adrenoceptors and can be inhibited by calcium entry blockers. This implies that contractile responses of these resistance vessels to alpha 1-adrenoceptor stimulation are not independent of the availability of extracellular calcium.
Centrally and locally elicited sympathetic vasoconstrictor responses were examined in 12 patients with symptoms and signs of cardiovascular autonomic dysfunction due to Parkinson's disease. The sympathetic reflex mechanisms were measured in skeletal muscle and subcutaneous tissue of the arm and leg using the 133-Xenon washout technique. This method allows differentiation between local and central sympathetic reflexes in different tissues. The results indicate an abolished centrally mediated vasoconstrictor response in skeletal muscle in the arm and a decreased response in skeletal muscle in the leg and in subcutaneous tissue. This is in agreement with an autonomic dysfunction located in the central nervous system. A possible spinal sympathetic reflex controlling blood flow in subcutaneous tissue and leg muscles is considered. The sympathetic vasoconstrictor responses in parkinsonian patients without autonomic failure were of normal magnitude and the responses were not affected by long-term levodopa treatment.
A mechanism by which acetylcholine (ACh) may elicit vasoconstrictor response in coronary vessels was studied in rat hearts perfused at a constant flow rate. In spontaneously beating hearts, bolus injections of ACh and carbachol (CCh) produced biphasic changes in coronary perfusion pressure (CPP): a transient increase at the initial period followed by a sustained decrease. In KCl-arrested hearts, ACh and CCh produced a monophasic increase in CPP, which was attenuated by either removal of endothelial cells by saponin or cyclooxygenase inhibition by diclofenac sodium. In the spontaneously beating heart, ACh-induced vasoconstriction was almost abolished by atropine (0.1 microM) and was markedly attenuated by an M2 antagonist, methoctramine (0.1 microM), but not by an M1 antagonist, pirenzepine (1 microM). Arecaidine propargyl ester (APE), an M2 agonist, produced coronary artery constriction which was attenuated by methoctramine (0.1 microM) but not by pirenzepine (0.1 microM) in both spontaneously beating and KCl-arrested hearts. McN-A-343, an M1 agonist, increased CPP in both beating and KCl-arrested hearts, but to a lesser degree than APE. These results suggest that the release of vasoconstrictor prostaglandins from endothelial cells contributes to the vasoconstrictor response to ACh in perfused rat coronary vessels, and the response to ACh appears to be mediated, in part, via the M2 subtype of muscarinic receptors.
The present study was undertaken to evaluate the contractile response of several E- and F-ring isoprostanes (IsoP) in human umbilical vein (HUV) and to investigate the role of the endothelium on the effect of 15-E2t-IsoP, the most potent vasoconstrictor isoprostane, in human vessels. HUV rings with or without endothelium were suspended in an organ bath for recording the isometric tension in response to different agonists. The inhibitors to be evaluated were applied 30 min before the addition of the agonist. All of the compounds tested produced concentration-dependent contractions when tested on HUV rings with endothelium. Although these compounds were equieffective, significant differences were observed in their potency, with U46619 being the most potent followed by 15-E2t-IsoP > 15-E1t-IsoP = 15-F2t-IsoP > 15-F1t-IsoP = 9-epi-15-F2t-IsoP in descending rank order of potency. 15-E2t-IsoP was the most potent of the isoprostanes evaluated and, therefore, the one employed in the present study. When intact endothelium HUV rings were used, 15-E2t-IsoP-induced contraction was unaffected by the endothelin-converting enzyme inhibitor, phosphoramidon (10 microM), suggesting that short-term endothelin-1 release is not involved in this response. However, the non-selective cyclooxygenase (COX) inhibitor, indomethacin (10 and 30 microM), and the COX-2 selective inhibitor, NS-398 (3, 10 and 30 microM) produced inhibitory effects on 15-E2t-IsoP-induced contraction of HUV rings with endothelium. These results indicate that COX-derived contractile prostanoids are involved in this effect. Furthermore, the apparent pKb values estimated for indomethacin (5.5) and NS-398 (5.4) suggest that the prostanoids involved are derived from the COX-2 isoenzyme pathway. On HUV rings with endothelium, the phospholipase A2 inhibitor, oleyloxyethyl phosphorylcholine (30 and 100 microM), induced an inhibitory effect on 15-E2t-IsoP-induced contraction, suggesting that the phospholipase A2 pathway is also involved in this effect. In addition, the thromboxane A2 synthase inhibitor furegrelate (10 and 30 microM) also inhibited 15-E2t-IsoP-induced contraction of HUV rings with endothelium, indicating that thromboxane A2 is one of the contractile prostanoids involved in this response. Endothelium denudation clearly diminished the vasoconstrictor potency of 15-E2t-IsoP, demonstrating that the endothelium releases a vasoconstrictor factor in response to 15-E2t-IsoP. The absence of an inhibitory effect at the highest concentration of furegrelate (30 microM) on 15-E2t-IsoP-induced contraction of HUV rings without endothelium suggested that endothelium is the source of thromboxane A2. We conclude that prostanoids derived from the COX-2 isoenzyme pathway participate in 15-E2t-IsoP-induced vasoconstriction of isolated HUV rings. Our results also indicate that endothelial thromboxane A2 is one of the prostanoids involved in this effect.
OBJECTIVES: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of alpha-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different alpha 1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these alpha 1-adrenoceptor antagonists in human subjects. METHOD: In thirteen healthy male subjects (20-42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). RESULTS: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The alpha 1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. CONCLUSION: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative alpha 1-adrenoceptor blocking potency of drugs.
OBJECTIVE: We hypothesized that the endothelial-derived relaxing factor nitric oxide may contribute to low resting vascular tone and may attenuate vasoconstrictor action in the human fetal-placental circulation. STUDY DESIGN: Isolated human placental cotyledons were dually perfused in vitro, and the effects of N-monomethyl-L-arginine and N-nitro-L-arginine (3 x 10(-4) mol/L), which are nonmetabolizable analogs of L-arginine, the substrate for nitric oxide synthase, on resting perfusion pressure and on the fetal-placental circulation preconstricted with U46619 (10(-8) mol/L) or endothelin-1 (10(-8) mol/L) were established. Responses before and after inhibition were compared by paired t test. The effects of glyceryl trinitrate (10(-6) mol/L), acetylcholine (10(-4) mol/L), the calcium ionophore A23187 (10(-6) mol/L), and histamine (10(-8) to 10(-4) mol/L) were also determined in the preconstricted fetal-placental circulation. RESULTS: Both N-monomethyl-L-arginine and N-nitro-L-arginine (3 x 10(-4) mol/L) increased resting perfusion pressure (p less than 0.06), and N-nitro-L-arginine promptly and significantly increased perfusion pressure in the fetal-placental circulation preconstricted with U46619 (p less than 0.0004) or endothelin-1 (p less than 0.06). Nitric oxide generated by addition of glyceryl trinitrate (10(-6) mol/L) attenuated the vasoconstrictor effects of U46619 (p less than 0.026) or endothelin-1 (p less than 0.01). Neither acetylcholine nor the calcium ionophore A23187 had an effect on the fetal-placental circulation, whereas bradykinin further increased perfusion pressure. Histamine only relaxed the preconstricted preparations at concentrations (10(-6) to 10(-4) mol/L) above those shown to release nitric oxide in other systems. CONCLUSION: The stimulus to nitric oxide generation in the fetal-placental circulation may be hydrodynamic. Nitric oxide appears to contribute to maintenance of basal vascular tone and to attenuate the actions of vasoconstrictors in this circulation.
Sympathetic neurotransmission can be modulated by prostaglandins in a number of tissues, but it is not known whether thromboxane A2 also influences neurotransmission. In this study, vasoconstrictor responses to electrical stimulation of the sympathetic nerves and to injection of noradrenaline were examined in the blood perfused mesentery of the rat in situ. The thromboxane synthetase inhibitor dazoxiben, infused into the perfusion circuit at 10-100 mumol/l, significantly inhibited constrictor responses to nerve stimulation and to injected noradrenaline and vasopressin. The cyclo-oxygenase inhibitor indomethacin (28 mumol/kg intravenously) had no effect on responses to nerve stimulation or noradrenaline, but pretreatment with indomethacin abolished the inhibitory effect of dazoxiben on vasoconstrictor responses. The thromboxane-mimetic (U46619, 10 nmol/l) slightly reduced responses to nerve stimulation (but not to noradrenaline), whereas prostacyclin (3-10 nmol/l) and PGE2 (3 nmol/l) markedly reduced responses both to nerve stimulation and to injections of noradrenaline. These prostanoids did not alter perfusion pressure at these concentrations. The data suggest that the inhibitory effect of dazoxiben on sympathetic neurotransmission is unlikely to be due directly to inhibition of thromboxane synthesis. Inhibition might result from diversion of endoperoxide metabolism to endogenous prostanoids that, in turn, inhibit activation of vasoconstrictor mechanisms.
Neuropeptide Y is a powerful vasoconstrictor in vivo; however, in vitro it shows weak constrictor effects. This discrepancy may have led to conflicting reports concerning the contractile effects of neuropeptide Y on isolated blood vessels. Using isolated rat tail and femoral artery segments neuropeptide Y (0.1-100 nM) did not induce any contractile response. However, if the catecholamine neuronal uptake blocker cocaine was added to the tissue bath, neuropeptide Y induced a contraction which could be fully blocked by prazosin (1000 nM). Furthermore, an age-dependent increase in the contraction to neuropeptide Y plus cocaine was observed. In conclusion, in the rat tail artery an apparent direct vasoconstrictor effect of neuropeptide Y occurs only in the presence of cocaine. Since this contraction can be fully blocked by prazosin, spontaneously released norepinephrine is an important component of the contraction. The discrepancy between in vivo and in vitro effects of neuropeptide Y may be explained in part by the presence of circulating vasoconstrictors.
The effects of prostaglandins (PG) D2 and E2 on vascular resistance and vasoconstrictor responses were compared in the feline mesenteric vascular bed under conditions of controlled flow so that changes in perfusion pressure directly reflect changes in vascular resistance. Infusions of PGD2 into the superior mesenteric artery significantly dilated the mesenteric vascular bed and inhibited vasoconstrictor responses to sympathetic nerve stimulation and intra-arterial injections of norepinephrine and angiotensin II. The inhibitory effects of PGD2 were reversible and dose-dependent. PGD2 inhibited responses to sympathetic nerve stimulation to a greater extent than responses to the pressor hormones. Infusion of PGE2 at similar doses dilated the mesenteric vascular bed but had little or no effect on vasoconstrictor responses to sympathetic nerve stimulation or pressor hormones. These data suggest that PGD2 possesses the ability to modulate responses to nerve stimulation and pressor hormones by both pre- and post-junctional actions in the feline mesenteric vascular bed.
The effects of PGE1 on vascular resistance, vasoconstrictor responses to sympathetic nerve stimulation and pressor hormones and vasodilator responses to bradykinin and nitroglycerin were investigated in the feline mesenteric vascular bed. Infusions of PGE1, 1.0 and 0.1 micrograms/min, into the superior mesenteric artery dilated the mesenteric vascular bed and markedly inhibited vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine and angiotensin and to vasodilator responses to bradykinin and nitroglycerin. The response to the highest dose of bradykinin was reversed to a pressor response during infusion of PGE1. In contrast, mesenteric perfusion pressure and vasoconstrictor responses to nerve stimulation and pressor hormones and vasodilator responses to bradykinin and nitroglycerin were unchanged during the lowest rate of infusion of PGE1, 0.01 microgram/min. When the decrease in (initial value) vascular resistance was taken into account by expressing vasodilator responses on a percent decrease basis, infusion of PGE1 reduced or reversed the vasodilator responses to bradykinin whereas the vasodilator responses to nitroglycerin were not altered. Results of these studies suggest that PGE1 may influence vasomotor tone and responses to pressor hormones and bradykinin in the mesenteric vascular bed of the cat.
Lesions of limb nerves in man may be associated with a variety of painful disorders with trophic changes described by the generic term 'reflex sympathetic dystrophy'. Our hypothesis is that pain and trophic changes are produced by an abnormal discharge pattern in postganglionic neurons supplying the limb (see refs. 3,24). In relation to this hypothesis, reflex patterns in postganglionic vasoconstrictor neurons supplying the skin (CVC) and the skeletal muscle (MVC) of the cat hindlimb were investigated at various times after a peripheral nerve lesion had been produced. These reflex patterns were compared with those in animals without nerve lesions (control preparations). The following lesions were made: cutting and ligating the superficial peroneal nerve (skin nerve) with subsequent neuroma formation, suturing the central stump of the superficial peroneal nerve to the peripheral stumps of muscle branches of the deep peroneal nerve, suturing the central stumps of muscle branches of the deep peroneal nerve to the peripheral stump of the superficial peroneal nerve, cutting and resuturing the superficial peroneal nerve, deafferentation of the whole hindlimb. The responses of vasoconstrictor neurons to stimulation of arterial chemoreceptors, arterial baroreceptors (cardiac rhythmicity of postganglionic activity) and cutaneous nociceptors were tested. In the animals with nerve lesions, the following groups of postganglionic vasoconstrictor neurons were analyzed: neurons projecting to the lesioned nerve, neurons projecting to hairy skin through an intact skin nerve (sural nerve) and neurons projecting to skeletal muscle through intact muscle nerves. In control preparations without nerve lesions, MVC neurons were excited by stimulation of arterial chemoreceptors and cutaneous nociceptors and inhibited by stimulation of arterial baroreceptors. Most CVC neurons were inhibited by stimulation of chemoreceptors and nociceptors and weakly inhibited by stimulation of baroreceptors. In animals with nerve lesions a and b, many CVC neurons in the lesioned nerves, as well as in the non-lesioned cutaneous nerve nearby, behaved in the same manner as MVC neurons. With respect to the control, this difference proved to be statistically significant. In preparations with lesions a, b and c, MVC neurons did not change their reflex patterns. After nerve lesions d and e, no major changes of reflex patterns were observed in CVC and MVC neurons. The inhibitory influence of arterial baroreceptors on CVC activity decreased in deafferented preparations (lesion e).(ABSTRACT TRUNCATED AT 400 WORDS)